Targeting adipose tissue via systemic gene therapy.
Targeting adipose tissue via systemic gene therapy.
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DOI：
10.1038/gt.2014.38
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发表时间：
2014-07
期刊：
影响因子：
5.1
通讯作者：
Reilly, M. P.
中科院分区：
文献类型：
--
作者：
O'Neill, S. M.;Hinkle, C.;Chen, S-J;Sandhu, A.;Hovhannisyan, R.;Stephan, S.;Lagor, W. R.;Ahima, R. S.;Johnston, J. C.;Reilly, M. P.
脂肪组织在能量和代谢稳态中起着关键作用，但调整技术以调节体内脂肪功能是具有挑战性的。在这里，我们开发了一种体内，系统的方法，基因转移，特别是针对脂肪组织使用腺相关病毒（AAV）载体。我们构建了含有CMV启动子调控的报告基因的AAV载体，使用多种AAV血清型将载体静脉内注射给成年小鼠，并确定AAV 2/8最佳靶向脂肪组织。改变载体以包含脂联素启动子/增强子元件和肝脏特异性microRNA-122靶位点，限制了报告基因在脂肪组织中的表达。作为功效的证明，将瘦素基因并入脂肪靶向表达载体中，包装到AAV 2/8中，并静脉内施用给9-10周龄ob/ob小鼠。在8周的时间内测量表型变化。瘦素mRNA和蛋白在脂肪组织中表达，瘦素蛋白分泌到血浆中。小鼠的反应是体重增加逆转，高胰岛素血症减少，葡萄糖耐量改善。AAV 2/8介导的脂肪靶向表达载体的全身递送可以替代脂肪组织中缺乏的基因并纠正人类疾病的小鼠模型，证明了脂肪疾病的实验应用和治疗潜力。
Adipose tissue plays a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing CMV promoter regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8, and administered intravenously to 9-10 week old ob/ob mice. Phenotypic changes were measured over an eight week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia, and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.
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影响因子：
29
作者：
Cortés VA;Curtis DE;Sukumaran S;Shao X;Parameswara V;Rashid S;Smith AR;Ren J;Esser V;Hammer RE;Agarwal AK;Horton JD;Garg A
通讯作者：
Garg A
影响因子：
4
作者：
Klebanov, S;Astle, CM;Harrison, DE
通讯作者：
Harrison, DE
影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
4.2
作者：
Kassim, Sadik H.;Li, Hui;Rader, Daniel J.
通讯作者：
Rader, Daniel J.
DOI：
10.1073/pnas.182412299
发表时间：
2002-09-03
影响因子：
11.1
作者：
Gao, GP;Alvira, MR;Wilson, JM
通讯作者：
Wilson, JM